期刊
IMMUNITY
卷 38, 期 2, 页码 285-295出版社
CELL PRESS
DOI: 10.1016/j.immuni.2013.01.008
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资金
- British Heart Foundation [FS/09/005/26845, PG/06/024/20354, RG 04/001]
- NIHR Cambridge BRC
- British Heart Foundation [FS/09/005/26845, FS/13/3/30038, RG/08/009/25841] Funding Source: researchfish
Necrosis can induce profound inflammation or be clinically silent. However, the mechanisms underlying such tissue specificity are unknown. Interleukin-1 alpha (IL-1 alpha) is a key danger signal released upon necrosis that exerts effects on both innate and adaptive immunity and is considered to be constitutively active. In contrast, we have shown that necrosis-induced IL-1 alpha activity is tightly controlled in a cell type-specific manner. Most cell types examined expressed a cytosolic IL-1 receptor 2 (IL-1R2) whose binding to pro-IL-1 alpha inhibited its cytokine activity. In cell types exhibiting a silent necrotic phenotype, IL-1R2 remained associated with pro-IL-1 alpha. Cell types possessing inflammatory necrotic phenotypes either lacked IL-1R2 or had activated caspase-1 before necrosis, which degraded and dissociated IL-1R2 from pro-IL-1 alpha. Full IL-1 alpha activity required cleavage by calpain after necrosis, which increased its affinity for IL-1 receptor 1. Thus, we report a cell type-dependent process that fundamentally governs IL-1 alpha activity postnecrosis and the mechanism allowing conditional release of this blockade.
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